Inclusion-Interaction Assembly Strategy for Constructing pH/Redox Responsive Micelles for Controlled Release of 6-Mercaptopurine

Abstract

An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.